Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor.

نویسندگان

  • Pamela Farrell
  • Lihong Shi
  • Jennifer Matuszkiewicz
  • Deepika Balakrishna
  • Takashi Hoshino
  • Lilly Zhang
  • Sarah Elliott
  • Robyn Fabrey
  • Bumsup Lee
  • Petro Halkowycz
  • BiChing Sang
  • Seigo Ishino
  • Toshiyuki Nomura
  • Mika Teratani
  • Yoshikazu Ohta
  • Charles Grimshaw
  • Bheema Paraselli
  • Takashi Satou
  • Ron de Jong
چکیده

Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Cancer Therapeutics Insights Biological Characterization of TAK-901, an Investigational, Novel, Multitargeted Aurora B Kinase Inhibitor

Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, b...

متن کامل

Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells.

BACKGROUND Aurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models. MATERIALS AND METHODS We conducted a synthetic lethal siRNA screening to identify the genes that, when silenc...

متن کامل

Predicting response to HER2 kinase inhibition

Comment on: Takagi S, Banno H, Hayashi A, Tamura T, Ishikawa T, Ohta Y. HER2 and HER3 cooperatively regulate cancer cell growth and determine sensitivity to the novel investigational EGFR/HER2 kinase inhibitor TAK-285. Oncoscience. 2014; 1:196-204.

متن کامل

Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide.

PURPOSE Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3. EXPERIMENTAL D...

متن کامل

Cancer Therapy: Preclinical Antimyeloma Activity of a Multitargeted Kinase Inhibitor, AT9283, via Potent Aurora Kinase and STAT3 Inhibition Either Alone or in Combination with Lenalidomide

Purpose: Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3. Experimental De...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular cancer therapeutics

دوره 12 4  شماره 

صفحات  -

تاریخ انتشار 2013